scholarly journals Cognitive aging is associated with redistribution of synaptic weights in the hippocampus

2021 ◽  
Vol 118 (8) ◽  
pp. e1921481118
Author(s):  
Eric W. Buss ◽  
Nicola J. Corbett ◽  
Joshua G. Roberts ◽  
Natividad Ybarra ◽  
Timothy F. Musial ◽  
...  
Keyword(s):  
Young Adult ◽  
Cognitive Aging ◽  
Pyramidal Neurons ◽  
Eyeblink Conditioning ◽  
Maze Learning ◽  
Aged Rats ◽  
Chronological Aging ◽  
Network Function ◽  
Neurobiological Substrates ◽  
Hippocampal Ca3

Behaviors that rely on the hippocampus are particularly susceptible to chronological aging, with many aged animals (including humans) maintaining cognition at a young adult-like level, but many others the same age showing marked impairments. It is unclear whether the ability to maintain cognition over time is attributable to brain maintenance, sufficient cognitive reserve, compensatory changes in network function, or some combination thereof. While network dysfunction within the hippocampal circuit of aged, learning-impaired animals is well-documented, its neurobiological substrates remain elusive. Here we show that the synaptic architecture of hippocampal regions CA1 and CA3 is maintained in a young adult-like state in aged rats that performed comparably to their young adult counterparts in both trace eyeblink conditioning and Morris water maze learning. In contrast, among learning-impaired, but equally aged rats, we found that a redistribution of synaptic weights amplifies the influence of autoassociational connections among CA3 pyramidal neurons, yet reduces the synaptic input onto these same neurons from the dentate gyrus. Notably, synapses within hippocampal region CA1 showed no group differences regardless of cognitive ability. Taking the data together, we find the imbalanced synaptic weights within hippocampal CA3 provide a substrate that can explain the abnormal firing characteristics of both CA3 and CA1 pyramidal neurons in aged, learning-impaired rats. Furthermore, our work provides some clarity with regard to how some animals cognitively age successfully, while others’ lifespans outlast their “mindspans.”

scholarly journals Neurotrophic factor-α1, a novel tropin is critical for the prevention of stress-induced hippocampal CA3 cell death and cognitive dysfunction in mice: comparison to BDNF

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lan Xiao ◽  
Vinay Kumar Sharma ◽  
Leila Toulabi ◽  
Xuyu Yang ◽  
Cheol Lee ◽  
...  
Keyword(s):  
Cell Death ◽  
Learning And Memory ◽  
Cognitive Dysfunction ◽  
Neurotrophic Factor ◽  
Maternal Separation ◽  
Pyramidal Neurons ◽  
Neuroprotective Activity ◽  
Weaning Stress ◽  
Hippocampal Ca3 ◽  
Ca3 Neurons

AbstractStress leads to brain pathology including hippocampal degeneration, cognitive dysfunction, and potential mood disorders. Hippocampal CA3, a most stress-vulnerable region, consists of pyramidal neurons that regulate cognitive functions e.g. learning and memory. These CA3 neurons express high levels of the neuroprotective protein, neurotrophic factor-α1 (NF-α1), also known as carboxypeptidase E (CPE), and receive contacts from granule cell projections that release BDNF which has neuroprotective activity. Whether NF-α1-CPE and/or BDNF are critical in protecting these CA3 neurons against severe stress-induced cell death is unknown. Here we show that social combined with the physical stress of maternal separation, ear tagging, and tail snipping at weaning in 3-week-old mice lacking NF-α1-CPE, led to complete hippocampal CA3 degeneration, despite having BDNF and active phosphorylated TrkB receptor levels similar to WT animals. Mice administered TrkB inhibitor, ANA12 which blocked TrkB phosphorylation showed no degeneration of the CA3 neurons after the weaning stress paradigm. Furthermore, transgenic knock-in mice expressing CPE-E342Q, an enzymatically inactive form, replacing NF-α1-CPE, showed no CA3 degeneration and exhibited normal learning and memory after the weaning stress, unlike NF-α1-CPE-KO mice. Mechanistically, we showed that radio-labeled NF-α1-CPE bound HT22 hippocampal cells in a saturable manner and with high affinity (Kd = 4.37 nM). Subsequently, treatment of the HT22cpe−/− cells with NF-α1-CPE or CPE-E342Q equivalently activated ERK signaling and increased BCL2 expression to protect these neurons against H2O2-or glutamate-induced cytotoxicity. Our findings show that NF-α1-CPE is more critical compared to BDNF in protecting CA3 pyramidal neurons against stress-induced cell death and cognitive dysfunction, independent of its enzymatic activity.

scholarly journals Liraglutide modulates GABAergic signaling in rat hippocampal CA3 pyramidal neurons predominantly by presynaptic mechanism

2017 ◽  
Vol 18 (1) ◽  
Author(s):  
Omar Babateen ◽  
Sergiy V. Korol ◽  
Zhe Jin ◽  
Amol K. Bhandage ◽  
Aikeremu Ahemaiti ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Hippocampal Ca3 ◽  
Ca3 Pyramidal Neurons

scholarly journals Computational Analysis of the Impact of Chronic Stress on Intrinsic and Synaptic Excitability in the Hippocampus

2010 ◽  
Vol 103 (6) ◽  
pp. 3070-3083 ◽  
Author(s):  
Rishikesh Narayanan ◽  
Sumantra Chattarji
Keyword(s):  
Chronic Stress ◽  
Pyramidal Neurons ◽  
Three Dimensional ◽  
Input Resistance ◽  
Synaptic Potentiation ◽  
Synaptic Inputs ◽  
Hippocampal Ca3 ◽  
Ca3 Pyramidal Neurons ◽  
Dendritic Atrophy ◽  
The Impact

Dendritic atrophy and impaired long-term synaptic potentiation (LTP) are hallmarks of chronic stress-induced plasticity in the hippocampus. It has been hypothesized that these disparate structural and physiological correlates of stress lead to hippocampal dysfunction by reducing postsynaptic dendritic surface, thereby adversely affecting the availability of synaptic inputs and suppressing LTP. Here we examine the validity of this framework using biophysical models of hippocampal CA3 pyramidal neurons. To statistically match with the experimentally observed region specificity of stress-induced atrophy, we use an algorithm to systematically prune three-dimensional reconstructions of CA3 pyramidal neurons. Using this algorithm, we build a biophysically realistic computational model to analyze the effects of stress on intrinsic and synaptic excitability. We find that stress-induced atrophy of CA3 dendrites leads to an increase in input resistance, which depends exponentially on the percentage of neuronal atrophy. This increase translates directly into higher spiking frequencies in response to both somatic current injections and synaptic inputs at various locations along the dendritic arbor. Remarkably, we also find that the dendritic regions that manifest atrophy-induced synaptic hyperexcitability are governed by the region specificity of the underlying dendritic atrophy. Coupled with experimentally observed modulation of N-methyl-d-aspartate receptor currents, such hyperexcitability could tilt the balance of plasticity mechanisms in favor of synaptic potentiation over depression. Thus paradoxically, our results suggest that stress may impair hippocampal learning and memory, not by directly inhibiting LTP, but because of stress-induced facilitation of intrinsic and synaptic excitability and the consequent imbalance in bidirectional synaptic plasticity.

scholarly journals Synapse type-specific proteomic dissection identifies IgSF8 as a hippocampal CA3 microcircuit organizer

2019 ◽  
Author(s):  
Nuno Apóstolo ◽  
Samuel N. Smukowski ◽  
Jeroen Vanderlinden ◽  
Giuseppe Condomitti ◽  
Vasily Rybakin ◽  
...  
Keyword(s):  
Cell Surface ◽  
Pyramidal Neurons ◽  
Mossy Fiber ◽  
Surface Protein ◽  
Guidance Cue ◽  
Hippocampal Ca3 ◽  
Cell Surface Interactions ◽  
Ca3 Pyramidal Neurons ◽  
Ca3 Neurons ◽  
Multiple Ligand

SummarySynaptic diversity is a key feature of neural circuits. The structural and functional diversity of closely spaced inputs converging on the same neuron suggests that cell-surface interactions are essential in organizing input properties. Here, we analyzed the cell-surface protein (CSP) composition of hippocampal mossy fiber (MF) inputs on CA3 pyramidal neurons to identify regulators of MF-CA3 synapse properties. We uncover a rich cell-surface repertoire that includes adhesion proteins, guidance cue receptors, extracellular matrix (ECM) proteins, and uncharacterized CSPs. Interactome screening reveals multiple ligand-receptor modules and identifies ECM protein Tenascin-R (TenR) as a ligand of the uncharacterized neuronal receptor IgSF8. Presynaptic Igsf8 deletion impairs MF-CA3 synaptic architecture and robustly decreases the density of bouton filopodia that provide feedforward inhibition of CA3 neurons. Consequently, loss of IgSF8 increases CA3 neuron excitability. Our findings identify IgSF8 as a regulator of CA3 microcircuit development and suggest that combinations of CSP modules define input identity.

Effects of isoflurane on prefrontal acetylcholine release and hypothalamic Fos response in young adult and aged rats

2004 ◽  
Vol 190 (2) ◽  
pp. 535-543 ◽  
Author(s):  
A. Jansson ◽  
K. Olin ◽  
T. Yoshitake ◽  
B. Hagman ◽  
M.K. Herrington ◽  
...  
Keyword(s):  
Young Adult ◽  
Acetylcholine Release ◽  
Aged Rats
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